Department of Anatomy, Hebei Medical University, Shijiazhuang, P.R. China.
Neuroscience Research Center, Hebei Medical University, Shijiazhuang, P.R. China.
J Alzheimers Dis. 2022;88(2):771-785. doi: 10.3233/JAD-220227.
The activation of microglia and neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD), but the exact roles of microglia and the underlying mechanisms remain unclear.
To clarify how the metabolic reprogramming of microglia induce by amyloid-β (Aβ)1-42 to affect the release of proinflammatory cytokines in AD.
MTS assay was used to detect the viability of BV2 cells treated with different concentrations of Aβ1-42 for different periods of time. The expression levels of proinflammatory cytokines were determined by qRT-PCR and western blot assay in BV2 cells and hippocampus of mice. RNA sequencing was applied to evaluate the gene expression profiles in response to HK2 knockdown in BV2 cells treated with Aβ1-42.
Low concentrations of Aβ1-42 increased the viability of BV2 cells and promoted the release of proinflammatory cytokines, and this process is accompanied by increased glycolysis. Inhibition of glycolysis significantly downregulated the release of proinflammatory cytokines in BV2 cells and hippocampus of mice treated with Aβ1-42. The results of RNA sequencing revealed the expression of chemokine ligand 2 (Cxcl2) and ephrin receptor tyrosine kinase A2 (EphA2) were significantly downregulated when knocked down HK2 in BV2 cells. Subsequently, the expression of proinflammatory cytokines was downregulated in BV2 cell after knocking down EphA2.
This study demonstrated that EphA2/p38 MAPK pathway is involved the release of proinflammatory cytokines in microglia induced by Aβ1-42 in AD, which is accompanied by metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis.
小胶质细胞的激活和神经炎症与阿尔茨海默病（AD）的发病机制有关，但小胶质细胞的确切作用和潜在机制仍不清楚。
阐明淀粉样蛋白β（Aβ）1-42 诱导的小胶质细胞代谢重编程如何影响 AD 中小胶质细胞促炎细胞因子的释放。
用 MTS 法检测不同浓度 Aβ1-42 作用不同时间对 BV2 细胞活力的影响。qRT-PCR 和 Western blot 检测 BV2 细胞和小鼠海马中促炎细胞因子的表达水平。应用 RNA 测序评估 HK2 敲低后 Aβ1-42 处理的 BV2 细胞中的基因表达谱。
低浓度 Aβ1-42 增加了 BV2 细胞的活力并促进了促炎细胞因子的释放，这一过程伴随着糖酵解的增加。抑制糖酵解显著下调了 Aβ1-42 处理的 BV2 细胞和小鼠海马中促炎细胞因子的释放。RNA 测序结果显示，HK2 敲低后 BV2 细胞中趋化因子配体 2（Cxcl2）和 Eph 受体酪氨酸激酶 A2（EphA2）的表达明显下调。随后，EphA2 敲低后，BV2 细胞中的促炎细胞因子表达下调。
本研究表明，EphA2/p38 MAPK 通路参与了 Aβ1-42 诱导的 AD 中小胶质细胞促炎细胞因子的释放，伴随着从氧化磷酸化（OXPHOS）到糖酵解的代谢重编程。
